Determining the effects of "bath salts" on cognitive control and functional brain connectivity

摘要 “浴盐”或合成卡西诺酮类药物长期使用的潜力，改变认知等行为的能力 大脑的控制和变化使他们成为一个重大的医疗保健问题。最有害的浴缸之一 盐为3，4-亚甲基二氧基吡喃丙酮(MDPV)。MDPV的不良行为影响可持续数天至- 几周可能是由于多巴胺神经传递的改变。对药物的研究表明，MDPV是 在药理上与可卡因相似，但持续时间更长。然而，MDPV的一个重要的未被探索的方面是 它如何改变认知控制，以及认知控制的变化是否构成了一些最严重的 使用MDPV的行为结果。认知控制指的是一系列心理过程，驱动着 目标导向行为的组织和调解。在这项拨款中，两个特定的认知控制领域 兴趣是灵活性和冲动。这两个子过程在物质使用障碍中受到损害 并可能导致不受控制的寻毒行为。使用功能磁共振成像，我们最近显示，在24小时后 大鼠急性给予MDPV引起大脑连接增加，特别是在额叶皮质 眼眶前额区(ORF)、边缘下区(IL)、前庭区(PL)和皮质下奖赏区等区域，包括 纹状体、杏仁核和伏隔核(NAC)。这些连接方面的变化可能是一些 MDPV最危险的效应是导致认知控制脑连接的长期变化 电路。因此，我们假设MDPV的持续自我管理将增加功能 额叶皮质(PL、IL和ORF)、丘脑、杏仁核和NAC之间的连接导致损害 在认知控制功能上。我们将使用被训练为长期自我管理的啮齿动物来验证这一假设 为期十天的MDPV。这项拟议的研究旨在解决我们在理解如何 MDPV破坏认知控制以及哪些大脑区域受影响最大，并计算连接 用功能磁共振成像检测大脑的变化。在这个项目中，候选人将评估认知控制的两个子过程， 冲动和灵活性。将分析有关功能连接性变化的行为 纵向静息状态功能磁共振成像(RsfMRI)数据，以及使用活动的神经元性能依赖活动 调节大鼠细胞骨架相关基因(Arc)的mRNA表达。开展拟议的研究将 允许候选人在独立的研究生涯中整合rsfMRI的纵向研究 药物使用障碍研究的连接性、行为学和弧形细胞分析。

Abstract “Bath salts” or synthetic cathinones drugs potential of chronic use, ability to alter behaviors like cognitive control and alterations in the brain makes them a significant healthcare concern. One of the most harmful bath salts is 3,4-methylenedioxypyrovalerone (MDPV). The adverse behavioral effects of MDPV can last days-to- weeks possibly due to alteration in dopamine neurotransmissions. Research into drug has shown that MDPV is similar pharmacologically to cocaine but longer lasting. However, an essential unexplored aspect of MDPV is how it alters cognitive control and whether changed cognitive control underlies some of the most severe behavioral outcomes of MDPV use. Cognitive control refers to a set of mental processes driving the organization and mediation of goal-oriented behavior. In this grant, two specific cognitive control domains of interest are flexibility and impulsivity. These two subprocesses are compromised in substance use disorders and can lead to uncontrolled drug-seeking behavior. Using fMRI, we recently showed that after 24 hours an acute MDPV administration in rats caused an increase in brain connectivity specifically in frontal cortical regions such as orbitofrontal (OrF), infralimbic (IL), prelimbic (PL) and subcortical reward regions including striatum, amygdala, and nucleus accumbens (NAc). These changes in connectivity could underlie some of the most dangerous effects of MDPV by inducing long-lasting changes in the connectivity of cognitive control brain circuitry. Therefore, we hypothesize that sustained self-administration of MDPV will increase functional connectivity between the frontal cortex (PL, IL, and OrF), thalamus, amygdala, and NAc leading to impairments in cognitive control functions. We will test this hypothesis using rodents trained to chronically self-administer MDPV for ten days. The proposed research is designed to address existing gaps in our understanding of how MDPV undermines cognitive control and which brain regions are most affected and calculating connectivity changes in the brain with fMRI. In this project, the candidate will assess two subprocesses of cognitive control, impulsivity, and flexibility. The behavior will be analyzed concerning functional connectivity changes of longitudinal resting state fMRI (rsfMRI) data, and neuronal performance-dependent activity using activity regulated cytoskeletal-associated gene (Arc) mRNA expression in rats. Carrying out the proposed research will permit the candidate to incur in an independent research career integrating longitudinal studies of rsfMRI connectivity, behavioral, and Arc cellular analysis into studies of drug use disorders.